Side-to-side nerve bridges reduce muscle atrophy after peripheral nerve injury in a rodent model

Abstract

Background

Peripheral nerve injury can result in muscle atrophy and long-term disability. We hypothesize that creating a side-to-side bridge to link an injured nerve with a healthy nerve will reduce muscle atrophy and improve muscle function.

Methods

Sprague-Dawley rats were divided into four groups (n = 7 per group). Group 1: transection only—a 10-mm gap was created in the proximal tibial nerve; group 2: transected plus repaired—the transected tibial nerve was repaired; group 3: transected plus repaired plus nerve bridge—transected nerve repaired with a distal nerve bridge between the tibial and peroneal nerves via epineurial windows; and group 4: transected plus nerve bridge—transected tibial nerve left unrepaired and distal bridge added. Gait was assessed every 2 wk. At 90 d the following measures were determined: gastrocnemius mass, muscle and nerve nuclear density, and axonal infiltration into the nerve bridge.

Results

Groups 3 and 4 had greater improvements in walking track recovery than groups 1 and 2. Group 3's gastrocnemius muscles exhibited the least amount of atrophy. Groups 1, 2, and 4 exhibited greater histologic appearance of muscle breakdown compared with group 3 and control muscle. Finally, most bridges in groups 3 and 4 had neuronal sprouting via the epineurial windows.

Conclusions

Our study demonstrated reduced muscle atrophy with a side-to-side nerve bridge in the setting of peripheral nerve injury. These results support the application of novel side-to-side bridges in combination with traditional end-to-end neurorrhaphy to preserve muscle viability after peripheral nerve injuries.

Introduction

There is an enormous clinical need for improved outcomes after nerve repair in the setting of trauma, fractures, and nerve plexus injuries [1], [2]. Axonal regeneration is a slow process occurring at approximately 1 mm/d [3]. In the case of proximal peripheral nerve injury, the process of regeneration and reinnervation may take years because of the large distance from the point of injury to the site of distal muscle innervation. During this time, the denervated end organs undergo histologic changes that are consistent with muscle atrophy and infiltration of fibrous tissue [3]. These changes lead to impaired physiological function, resulting in long-term disabilities.

Currently, the gold standard for repairing nerve gaps are autologous nerve grafts. Unfortunately, this technique is associated with significant donor site morbidity, neuromas, and variable ability to prevent muscle atrophy at the end organ. One strategy to minimize donor site morbidity is to use synthetic conduits, which can bridge short gaps. Present research aims to increase the gap length that can be successfully bridged by using growth factors, stem cells, or a combination of the two along with synthetic conduits [4]. Preliminary results using these enhanced conduits are promising, however, distant muscle atrophy remains a problem.

Another strategy to minimize muscle atrophy is the coaptation of an injured nerve to a healthy donor nerve in an end-to-side fashion. This technique can reinnervate a paralyzed muscle and minimize muscle atrophy. The use of end-to-side neurorrhaphy has resulted in improvements in muscle mass through motor neuron collateral sprouting via an epineurial window on the healthy donor nerve to the recipient nerve [5], [6], [7]. As an extension of end-to-side nerve coaptation, we propose that connecting a healthy donor nerve to an injured nerve in a side-side fashion via a synthetic conduit will result in similar improvements in muscle mass. In the setting of a proximally injured and repaired peripheral nerve, these side-to-side connections may function to babysit the muscle during which time the damaged nerve is regenerating. We have therefore designed the present study to combine the traditional end-to-end neurorrhaphy with a distal side-to-side synthetic nerve bridge. We hypothesize that connecting a healthy nerve to a proximally damaged nerve via a distal side-to-side nerve bridge through epineurial windows will reduce muscle atrophy during which time the damaged nerve is regenerating. This combined method is projected to reduce muscle atrophy and improve muscle function.